Juha Punnonen

Increased levels of interleukin-6 and interleukin-10 in the peritoneal fluid of patients with endometriosis ☆ ☆☆ ★

OBJECTIVE The levels of interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-10, and granulocyte-macrophage colony-stimulating factor were measured in the peritoneal fluid of 15 patients with endometriosis to characterize the type of immune response that occurs at the site of endometriosis. STUDY DESIGN Cytokine levels in peritoneal fluid obtained during laparoscopy from 15 patients and 12 controls undergoing tubal ligation were determined by enzyme-linked immunosorbent assay. RESULTS The mean levels of interleukin-6 in patients with endometriosis and controls were 797 +/- 407 pg/ml and 133 +/- 38 pg/ml, respectively (p < 0.02). Similarly, the mean concentration of interleukin-10 in peritoneal fluids of patients with endometriosis was significantly higher than that of controls (241 +/- 38 vs 128 +/- 21, p < 0.05). The levels of interleukin-2, interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating factor were not significantly different between the two study groups. CONCLUSIONS The levels of interleukin-6 and interleukin-10 are increased in the peritoneal fluids of patients with endometriosis, suggesting enhanced macrophage activity in these patients. Increased interleukin-6 and interleukin-10 production may partially contribute to the disturbed immune regulation observed in patients with endometriosis.

SLAM and its role in T cell activation and Th cell responses.

Following the initial events of T cell activation, triggered by binding of specific peptide‐MHC complex to the TCR for antigen and engagement of costimulatory molecules, a number of activation molecules are expressed on the cell surface. Many of these molecules regulate T cell function. T‐T cell interactions and the interaction of T cells with other cells. One such molecule is SLAM, a multifunctional 70 kDa glycoprotein member of the Ig superfamily with multiple isoforms. SLAM is rapidly induced on natve T cells and B cells following activation. Engagement of SLAM by a specific antibody (mAb A12) results in IL‐2‐independent T cell expansion and induction/up‐regulation of IFN‐γ by activated T cells, including Th2 cells. SLAM was found to be a high‐affinity self‐ligand mediating molecular and cellular homophilic interactions. In this review we discuss SLAM as a receptor involved in T cell expansion and in directing immune responses to a Th0‐Th 1 pathway.

Regulation of IgE synthesis by cytokines

Considerable progress has been made in our understanding of the mechanisms underlying regulation of human IgE synthesis. Interleukin-4 induces IgE production specifically, but costimulatory signals provided by T cells are required. Other cytokines modulate interleukin-4-induced IgE synthesis. The roles of T cells and cytokines in regulating IgE switching are discussed.

Cytokine production profiles in the peritoneal fluids of patients with malignant or benign gynecologic tumors

Cytokines play a key role in the regulation of cells of the immune system and also have been implicated in the pathogenesis of malignant diseases. Some cytokines have been shown to have potential in the diagnosis of cancer.

Regulation of copper/zinc and manganese superoxide dismutase by UVB irradiation, oxidative stress and cytokines

We have examined the effects of UVB irradiation, oxidative stress and cytokines on the antioxidant enzymes copper/zinc and manganese superoxide dismutase (CuZnSOD and MnSOD) in HeLa cells. A single dose of UVB irradiation regulated dose-dependently the expression of the 4 kb transcript of MnSOD although it did not have any significant effect on MnSOD enzymatic activity. In contrast, UVB irradiation reduced both the enzymatic activity and the expression of the 0.7 and 0.9 kb mRNA transcripts of CuZnSOD. The cytokines TNF-alpha (1 ng ml-1 and 10 ng ml-1) and IL-6 (100 U ml-1) induced MnSOD activity, and TNF-alpha also upregulated MnSOD mRNA expression. Interestingly, genistein, a soy isoflavone and a tyrosine kinase inhibitor, was able to inhibit the induction of Mn-SOD activity and mRNA expression by TNF-alpha. Enzymatic CuZnSOD activity was depressed by a high dose of H2O2 while IL-6 or TNF-alpha had no effect on CuZnSOD activity. Our results demonstrate that, in addition to enzyme activity level, UVB irradiation can regulate the superoxide dismutases at the mRNA level. We also suggest that UVB irradiation, oxidative stress and cytokines regulate differentially CuZnSOD and MnSOD, and that the activities and expression of these antioxidant enzymes are controlled by distinct mechanisms.

The effect of storage of antigen-coated polystyrene microwells on the detection of antibodies against Borrelia burgdorferi by enzyme immunoassay (EIA)

Qualitative and quantitative changes in the antigenic mosaic of coated solid-phase matrices occurring during storage may have a pronounced effect on the comparability of results obtained by enzyme immunoassay (EIA). We have used, as a model antigen for studying the effects of storage, a sonic extract of Borrelia burgdorferi and a totally automatic EIA procedure. The IgM antibody concentrations of the sera originally determined to be high decreased by almost one half during 1 weeks storage of the solid phase of 4 degrees C. In contrast, the IgM values of other sera, originally measured at medium or low, doubled upon storage. Thus, after storage the rank order of the sera was markedly affected compared to the values obtained with antigen freshly applied to the wells. In parallel determinations of IgG antibody levels the EIU relative unitage values of the test sera generally remained constant upon storage. The only exception was the serum with the highest original antibody concentration. Its relative antibody unitage more than tripled over the storage time. It is recommended that the coating of solid-phase matrices should be done immediately before each run in all EIAs where microbial extracts are used as antigens.

Interferon (IFN)‐α, IFN‐γ, interleukin (IL)‐2, and arachidonic acid metabolites modulate IL‐4‐induced IgE synthesis similarly in healthy persons and in atopic dermatitis patients

The role of cytokines and arachidonic acid metabolites in the regulation of IgE production in healthy persons and in atopic dermatitis patients with elevated IgE levels was studied. Interleukin‐4 (IL‐4) induced IgE production in peripheral blood mononuclear cells (PBMCs) of all donors, and no significant difference was found between the amounts of IgE produced by healthy persons and atopic dermatitis patients. Similarly, recombinant interferon (IFN)‐α and IFN‐γ, as well as IL‐2, inhibited IL‐4‐induced IgE production to a similar extent in both study groups. To evaluate the role of arachidonic acid (AA) metabolites in the regulation of IgE production, we added indomethacin, an inhibitor of the cyclooxygenase pathway, or nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway, to IL‐4‐treated cultures. Both indomethacin and NDGA strongly inhibited IL‐4‐induced IgE production. They also inhibited IL‐4‐induced IgG4 synthesis. No significant difference in the amount of inhibition was found between the two study groups. We were unable to restore the NDGA‐induced inhibition of IgE‐production by adding leukotrienes B4, C4, D4, or 5‐HETE to the NDGA‐treated cultures. PGE2 also failed to restore the indomethacin‐mediated inhibitory effect. Consequently, NDGA‐ and indomethacin‐mediated inhibitory effects do not appear to be mediated by any single factor studied. Collectively, our results show IFNs and IL‐2 to be similar in effect in the modulation of IL‐4‐induced IgE synthesis in healthy and atopic persons. In addition, our results show the importance of AA metabolites in the regulation of IgE and IgG4 synthesis in normal persons as well as in atopic dermatitis patients.

Regulation of the testis

The testicular cells are regulated by factors produced locally in the testis. These factors include peptide growth factors, pro-opiomelanocortin derivatives, neuropeptides and steroids. Several agents able to affect steroido- and spermatogenesis can also affect leukocytes and many of the testis-regulating factors are produced by immune cells, suggesting that testicular cells and leukocytes may interact. In the present article, the effects of various testicular cell and leukocyte produced factors on steroido- and spermatogenesis are reviewed. The possibility that leukocytes may produce substances able to affect the testicular functions suggests that inhibition of immune system activation in the testis may be important also for reasons other than protection of autoantigenic germ cells from an autoimmune attack.

Production of interleukin-1β and tumour necrosis factor-α in patients with benign or malignant ovarian tumours

SummaryTo assess the role of interleukin-1β (IL-1β) and tumour necrosis factorα (TNFα) in the physiological host defence mechanisms against malignancies, the production of these cytokines in sera, ascitic and cyst fluids and in the tumour tissues of patients with benign or malignant ovarian tumours was studied. IL-1β was found neither in the sera nor in the ascitic fluids of these patients. It was also virtually absent from the cyst fluid samples. However, a mean value of 790 pg IL-1β/g tumour was found. Like IL-1β, TNFα was virtually absent in the serum samples. It was, however, detectable in the ascitic and cyst fluids and tumour tissues. The TNFα concentrations were highest in the tumour tissues, with a mean level of 328 pg/g tumour. When comparing the level of IL-1β and TNFα in patients with benign tumours to that seen in patients with malignant tumours, no differences in production were observed, regardless of the origin of the test samples. Our results indicate the production of IL-1β and TNFα in patients with ovarian tumours. More importantly, the finding that the production of these cytokines in patients with benign tumours is similar to that in patients with malignant tumours supports the conclusion that the production of these cytokines is more a nonspecific indicator of an inflammatory process than a specific response to a malignant process.

Regulation of IgE synthesis by T cells and cytokines

Human IgE synthesis is tightly regulated by cytokines. IgE production by normal B cells is specifically induced by IL-4, but requires additional, yet to be defined, signals that are provided by CD4+ T cells. Single surface IgM+ B cells can be induced to proliferate and switch to IgG4 and IgE producing cells, indicating that the induction of IgE synthesis by IL-4 and CD4+ T cells reflects direct isotype switching. Although IL-4 is the sole inducing cytokine of IgE synthesis known thus far, multiple cytokines modulate IL-4 induced IgE synthesis in vitro. IFN-alpha, IFN-gamma TGF-beta and IL-10 are inhibitory, whereas IL-5, IL-6 and TNF-alpha act synergistically with IL-4. Results obtained with animal models, as well as from clinical studies in the human have indicated that IL-4, IFN-alpha and IFN-gamma are operational in vitro. Cocultivation of B cells with allergen-specific CD4+ T cell clones producing high levels of IL-4 and IL-5, but normal to undetectable levels of IL-2 and IFN-gamma, following activation resulted in the synthesis of IgE, in the absence of exogenously added IL-4. These results indicate that aberrant ratios of IL-4 and IFN-gamma production are sufficient for induction of IgE synthesis in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)